Synthesis of Theaflavins via Biomimetic Oxidative Coupling Reactions

Article abstract of DOI:10.1055/s-0032-1318131

Biomimetic synthesis of theaflavins from catechins was accomplished by using 2-nitrobenzenesulfonyl (Ns) as a protecting group for phenols to minimize undesired side reactions of the electron-rich aromatic rings. This enabled the construction of the complex benzotropolone core in a single-step oxidative coupling reaction. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1318131

LETTER
▌479
lSetyternthesis of Theaflavins via Biomimetic Oxidative Coupling Reactions
Synthesis of Theaflavins via Biomimetic Oxidative Couplings
Yusuke Kawabe, Yoshiyuki Aihara, Yoshitsugu Hirose, Asuka Sakurada, Atsushi Yoshida, Makoto Inai,
Tomohiro Asakawa, Yoshitaka Hamashima, Toshiyuki Kan*
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
Fax +81(54)2645745; E-mail: kant@u-shizuoka-ken.ac.jp
Received: 11.12.2012; Accepted after revision: 07.01.2013
catechins by means of biomimetic oxidative coupling
reactions.
Abstract: Biomimetic synthesis of theaflavins from catechins was
accomplished by using 2-nitrobenzenesulfonyl (Ns) as a protecting
group for phenols to minimize undesired side reactions of the
electron-rich aromatic rings. This enabled the construction of the
complex benzotropolone core in a single-step oxidative coupling
reaction.
OH
OH
OH
O
HO
O
Key words: theaflavins, 2-nitrobenzensulfonyl group, polyphenol,
OH
OH
biomimetic synthesis, benzotropolone
2,3-cis: theaflavin (1)
2,3-trans: neotheaflavin (2)
2
3
HO
O
Theaflavin (1; Figure 1), one of the polyphenols that are
major constituents of tea,1 is an oxidative dimer of cate-
chin derivatives2 and has various biological activities.3
Although many synthetic studies of catechin derivatives
have been reported,4 there are only a few reports of the
OH
OH
Figure 1 Structures of theaflavin (1) and neotheaflavin (2)
biomimetic synthesis of 1 using enzymatic oxidation.5 Re- Recently, we reported a regioselective synthesis of meth-
cently, Nakatsuka and Yanase’s group reported a novel ylated epigallocatechin gallate from epigallocatechin by
oxidative coupling of ortho-quinone 4 and pyrogallol de- utilizing Ns groups as protecting groups for phenols.9 For
rivative 5 based on the proposed biosynthetic route the synthesis of theaflavin, we initially investigated the
(Scheme 1).6 Although their model reactions proceeded in selective incorporation of Ns groups into the A-ring of
excellent yield, application of this approach to the synthe- catechin (CC) (9), epicatechin (EC) (10) and epigallo-
sis of theaflavin has not been reported to date,7 probably catechin (EGC) (11), as shown in Scheme 2.
because the oxidation precursors and theaflavin itself are
Regioselective protection of the A-ring with Ns groups
unstable under strongly oxidizing conditions. We have de-
was performed by utilizing the bridged boric ester 810 be-
veloped the 2-nitrobenzensulfonyl (Ns) group8 for pro-
tween neighboring phenolic hydroxyl groups on the B-
tecting reactive phenols, and we envisioned that
ring as an intermediate. Thus, the boric ester was formed
application of Ns group would enable the efficient synthe-
by treatment of 9 with boric acid in the presence of aque-
ous NaOH, and then reaction with NsCl followed by acid-
sis of theaflavins from catechins. Herein, we report the
syntheses of theaflavin (1) and its derivatives from
ic hydrolysis of boric ester provided 12 exclusively.
Similar reactions of 10 and 11 proceeded smoothly to pro-
OH
O
OH
O
Fetizon's reagent
CH2Cl2
3
4
O
O
O
OH
OH
OH
O
OH
O
OH
OH
+ H2O
– CO2
4
OH
5
OH
OH
6
7
Scheme 1 Coupling reaction of ortho-quinone 4 and pyrogallol derivative 5 reported by Nakatsuka and Yanase
SYNLETT 2013, 24, 0479–0482
Advanced online publication: 23.01.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1318131; Art ID: ST-2012-U1061-L
© Georg Thieme Verlag Stuttgart · New York

480
Y. Kawabe et al.
LETTER
OH
B
OH
OH
R
OH
R
boric acid
aq NaOH
HO
O
C
2
3
2
3
NsO
O
A
NsCl
toluene
pH 9.0 buffer
OH
OH
OH
ONs
Entry Catechin
Product
Yield (%)
O
B
1
9 R = H, 2,3-trans
10 R = H, 2,3-cis
11 R = OH, 2,3-cis
Ns-CC (12)
Ns-EC (13)
Ns-EGC (14)
70
63
52
O
2
3a
R
a Three equivalents of NsCl were used.
8
Scheme 2 Regioselective incorporation of Ns group into the A-ring of 9, 10 and 11
vide 13 and 14, respectively. Although the boric ester in- dation step from 17 to 18, although the precise mechanism
termediate of 11 has a phenolic hydroxyl group remaining remains unclear. After separation from 12 (generated by
on the B-ring, steric hindrance is expected to prevent its reduction of 15), deprotection of the Ns groups of 16 was
reaction with NsCl.
accomplished by treatment with thiophenol and cesium
carbonate to provide neotheaflavin (2).11 During the cou-
pling and deprotection processes, no appreciable de-
composition of benzotropolone was observed.
Having succeeded in selective protection of the A-ring,
the next challenge is oxidation of the catechol group in 12
and 13. First, we optimized the oxidation conditions using
12, which is derived from less expensive 9. As shown in
Scheme 3, the best result was obtained by oxidation with
Pb(OAc)4 in MeCN at 0 °C, affording the desired quinone
15 quantitatively. The use of Pb(OAc)4 as an oxidant of-
fers the advantage of easy removal of the reduced lead salt
from the reaction medium by filtration through Celite af-
ter completion of the reaction. Furthermore, the electron-
withdrawing nature of the Ns group would enhance the
stability of the A-ring in the presence of the strong oxidant
Pb(OAc)4. Although other oxidants, such as Fetizon’s re-
agent and PhI(OAc)2, were tested, the chemical yields
were unsatisfactory. Since the resulting ortho-quinone 15
was not stable on silica gel, crude 15, obtained by simple
filtration, was used directly in the next reaction.
ONs
OH
OH
PhSH
NsO
NsO
O
O
15
Cs2CO3
O
14
2
3 Å MS
MeCN–CH2Cl2
0 °C, H2O
50%
MeCN–DMF
55%
OH
OH
OH
ONs
16
Scheme 4 Synthesis of neotheaflavin (2) by oxidative coupling re-
action of 14 and 15
This benzotropolone ring-forming reaction was also ap-
plicable to the synthesis of theaflavin (1) and its deriva-
tives, as shown in Scheme 6. Upon treatment of Ns-
protected epicatechin (13) with Pb(OAc)4, the desired ox-
idation reaction proceeded smoothly to provide ortho-qui-
none 21. The coupling reaction with 14 was carried out
without purification of the ortho-quinone intermediate to
give a benzotropolone intermediate. Finally, deprotection
of the Ns groups afforded theaflavin (1). Decreased yield
of 1 in comparison with 2 might be a result of instability
of the ortho-quinone intermediate derived from cis-dihy-
drobenzopyran 13. This oxidation–coupling strategy was
also applied to pyrogallol (22) and gallate 24 to give 23
and 25, respectively (Scheme 6). Since compounds simi-
lar to 25, derived from oxidative coupling of gallate deriv-
atives, have been isolated from tea,12 this method should
be useful for synthesizing derivatives for SAR studies.
OH
O
OH
O
NsO
O
NsO
O
Pb(OAc)4
MeCN,
0 °C
filtration
quant.
OH
OH
ONs
ONs
12
15
Scheme 3 Oxidation of 12 to ortho-quinone 15
With 15 in hand, we tested the coupling reaction with py-
rogallol derivative 14 (Scheme 4). Gratifyingly, treatment
of three equivalents of 15 with 14 in a mixture of MeCN
and CH2Cl2, followed by addition of H2O, afforded the de-
sired compound 16 in moderate yield. Considering the re-
action mechanism illustrated in Scheme 5, at least two
equivalents of ortho-quinone should theoretically be con-
sumed in the oxidation steps of 17 to 18 and 19 to 20. Fur-
thermore, the addition of 3 Å MS to the reaction mixture
before the addition of H2O was essential for efficient con-
version. 3 Å MS might play a significant role in the oxi-
In summary, we have accomplished a short-step biomi-
metic syntheses of theaflavin (1), neotheaflavin (2) and
their derivatives by utilizing Ns as a protecting group for
phenols. As far as we know, this is the first example of the
Synlett 2013, 24, 479–482
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Theaflavins via Biomimetic Oxidative Couplings
481
H+
O
H
O
R2
OH
R2
OH
R1
OH
oxidation
H
OH
OH
O
H
OH
OH
R1
OH
H+
R1
O
H+
O
H+
O
O
H
O
R2
O
H+
R2
R1
O
OH
OH
R2
R1
H2O
H
OH
OH
oxidation
••
H+
OH
OH
R1
O
H
OH
OH
17
18
H+
R2
OH
O
R2
OH
OH
OH
R2
O
O
O
– CO2
oxidation
O
HO
O
H
R1
H
R1
R1
OH
H
OH
OH
OH
OH
19
20
Scheme 5 Proposed mechanism of the coupling reaction of quinone and pyrogallol according to Nakatsuka and Yanase
OH
O
OH
O
B
NsO
O
2
3
Pb(OAc)4
MeCN
NsO
O
2
3
A
OH
OH
ONs
ONs
catechin
2,3-cis: Ns-EC (13)
2,3-trans: Ns-CC (12)
OH
2,3-cis: 21
2,3-trans: 15
R2
OH
R2
OH
O
R1 = Ns
R1 = H
PhSH
OH
Cs2CO3
MeCN
DMF
R2Ar
R1O
OH
O
2
3 Å MS
OH
H2O
3
OH
OR1
Yield (%)
R2Ar
(2 steps from R2Ar)
Entry Catechin
Product
1a
2
3
13
12
12
14
1
11
22 R2 = H
23 (2,3-trans) 13
25 (2,3-trans) 24
24 R2 = CO2Me
a 2-H2NC6H4SH was used instead of PhSH.
Scheme 6 Synthesis of theaflavin (1) and its derivatives
chemical syntheses of theaflavins. Further application of
this approach is underway in our laboratory.
Acknowledgments
The authors thank Dr. Masayuki Suzuki (Mitsui Norin Co., Ltd) for
providing samples of (–)-EGC, (–)-EC and (–)-GC. This work was
financially supported by a grant from the Shizuoka Prefecture and
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 479–482

482
Y. Kawabe et al.
LETTER
Shizuoka City Collaboration of Regional Entities for the Advance-
ment of Technological Excellence, a grant from the Japan Science
and Technology Agency (JST), and a Grant-in-Aid for Scientific
Research on Priority Areas (No 12045232) from the Ministry of
Education, Culture, Sports, Science and Technology (MEXT) of Ja-
pan. We also thank Professors Tsutomu Nakayama, Masahiko Hara,
and Takeshi Ishii (Department of Food and Nutritional Science,
University of Shizuoka) for valuable discussions.
Vogel, M. Can. J. Chem. 1967, 45, 1949. (b) Nonaka, G.;
Hashimoto, F.; Nishioka, I. Chem. Pharm. Bull. 1986, 34,
61.
(8) For reviews of Ns-strategy, see: (a) Kan, T.; Fukuyama, T. J.
Synth. Org. Chem., Jpn. 2001, 59, 779. (b) Kan, T.;
Fukuyama, T. Chem. Commun. 2004, 353.
(9) Aihara, Y.; Yoshida, A.; Furuta, T.; Wakimoto, T.; Akizawa,
T.; Konishi, M.; Kan, T. Bioorg. Med. Chem. Lett. 2009, 19,
4171.
(10) Chang, J.; Chen, R.; Guo, R.; Dong, C.; Zhao, K. Helv.
Chem. Acta 2003, 86, 2239.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SuppInigfor
m
o
ti
(11) Synthetic Procedure for 2: To a solution of 12 (1.0 g, 1.5
mmol) in MeCN (15 mL) was added Pb(OAc)4 (806 mg, 4.5
mmol) at 0 °C. The resulting suspension was stirred for 10
min at 0 °C. The reaction mixture was added to benzene, and
then the mixture was filtered through a pad of Celite. Then
the filtrate was evaporated under reduced pressure, and the
resulting crude product 15 was dissolved in MeCN–CH2Cl2
(1:4, 25 mL). To the solution of 15 were added MS 3A (1.0
g) and 14 (342 mg, 505 μmol) in MeCN–CH2Cl2 (1:4, 10
mL) at 0 °C. The resulting suspension was stirred for 20 min
at 0 °C. After the addition of H2O the mixture was stirred for
5 min at r.t. The reaction mixture was filtered, and the filtrate
was extracted with EtOAc, the organic phase was washed
with H2O, and evaporated under reduced pressure. The
residue was purified by silica gel flash column
References and Notes
(1) (a) Yamamoto, T.; Juneja, L. R.; Chu, D.-C.; Kim, M.
Chemistry and Applications of Green Tea; CRC: Boca
Raton, 1997. (b) Stuart, E. C.; Scandlyn, M. J.; Rosengren,
R. J. Life Sci. 2006, 79, 2329.
(2) (a) Roberts, E. A. H. Chem. Ind. 1957, 1354. (b) Takino, Y.;
Ferretti, A.; Flanagan, V.; Gianturco, M.; Vogel, M.
Tetrahedron Lett. 1965, 4019.
(3) (a) Friedman, M.; Henika, P. R.; Levin, C. E.; Mandrell, R.
E.; Kozuku, N. J. Food Protection 2006, 69, 354.
(b) Lorenz, M.; Urban, J.; Engelhardt, U.; Baumann, G.;
Stangl, K.; Stangl, V. Basic Res. Cardiol. 2009, 104, 100.
(c) Wu, Y.-Y.; Li, W.; Xu, Y.; Jin, E.-H.; Tu, Y.-Y. J.
Zhejiang Univ.-Sci. B 2011, 12, 744. (d) Oka, Y.; Iwai, S.;
Amano, H.; Irie, Y.; Yatomi, K.; Ryu, K.; Yamada, S.;
Inagaki, K.; Oguchi, K. J. Pharmacol. Sci. 2012, 118, 55.
(4) For a review on recent progress in the synthesis of
flavonoids, see: Oyama, K.; Yoshida, K.; Kondo, T. Curr.
Org. Chem. 2011, 15, 2567.
(5) (a) Tanaka, T.; Mine, C.; Inoue, K.; Matsuda, M.; Kouno, I.
J. Agric. Food Chem. 2002, 50, 2142. (b) Sang, S.; Lambert,
J. D.; Tian, S.; Hong, J. Z.; Ryu, J.-H.; Stark, R. E.; Rosen,
R. T.; Huang, M.-T.; Yang, C. S.; Ho, C.-T. Bioorg. Med.
Chem. 2004, 12, 459. (c) Tu, Y. Y.; Xu, X. Q.; Xia, H. L.;
Watanabe, N. Biotechnol. Lett. 2005, 27, 269.
chromatography (CH2Cl2–MeOH, 98:2) to afford 16 (327
mg, 50%) as an orange amorphous solid.
To a suspension of Cs2CO3 (501 mg, 0.17 mmol) and
thiophenol (0.17 mL, 1.7 mmol) in MeCN–DMF (1:2, 2.7
mL) was added the solution of 16 (223 mg, 0.17 mmol) in
MeCN (3.0 mL) at 0 °C After stirring at 0 °C for 2 h, the
reaction was quenched with aq 1 M HCl and extracted with
EtOAc. The organic phase was evaporated under reduced
pressure. The residue was purified by preparative TLC
(CH2Cl2–MeOH, 9:1) to afford 2 (53 mg, 55%) as an orange
amorphous solid.
Spectral Data for 2: [α]D20 –122.1 (c = 0.20, acetone). 1H
NMR (500 MHz, acetone-d6): δ = 8.83 (br s, 1 H), 8.27 (s, 1
H), 7.77 (s, 1 H), 7.67 (s, 1 H), 6.08 (s, 1 H), 6.04 (s, 1 H),
5.96 (s, 1 H), 5.95 (s, 1 H), 5.62 (d, J = 5.0 Hz, 1 H), 5.02 (s,
1 H), 4.38 (br s, 1 H), 4.10–4.16 (m, 1 H), 2.75–3.00 (m, 3
H), 2.66 (dd, J = 16.0, 9.0 Hz, 1 H). HRMS (ESI): m/z [M +
Na]+ calcd for C29H24O12Na: 587.1159; found: 587.1130
(12) Itoh, N.; Katsube, Y.; Yamamoto, K.; Nakajima, N.;
Yoshida, K. Tetrahedron 2007, 63, 9488.
(6) (a) Yanase, E.; Sawaki, K.; Nakatsuka, S. Synlett 2005,
2661. (b) Professors Tanaka and Kouno reported direct
coupling reaction between quinones derived from EC and
EGC; see in: Tanaka, T.; Mine, C.; Inoue, K.; Matsuda, M.;
Kouno, I. J. Agric. Food Chem. 2002, 50, 2142.
(7) The chemical syntheses of epitheaflagallins by the coupling
reaction of 10 and pyrogallols were reported. See:
(a) Takino, Y.; Ferretti, A.; Flanagan, V.; Gianturco, M. A.;
Synlett 2013, 24, 479–482
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.